title: Fragment-based domain shuffling approach for the synthesis of pyran-based macrocycles.
abstract: Complexity and the presence of stereogenic centers have been correlated with success as compounds transition from discovery through the clinic. Here we describe the synthesis of a library of pyran-containing macrocycles with a high degree of structural complexity and up to five stereogenic centers. A key feature of the design strategy was to use a modular synthetic route with three fragments that can be readily interchanged or "shuffled" to produce subtly different variants with distinct molecular shapes. A total of 352 macrocycles were synthesized ranging in size from 14- to 16-membered rings. In order to facilitate the generation of stereostructure-activity relationships, the complete matrix of stereoisomers was prepared for each macrocycle. Solid-phase assisted parallel solution-phase techniques were employed to allow for rapid analogue generation. An intramolecular nitrile-activated nucleophilic aromatic substitution reaction was used for the key macrocyclization step.
authors.affiliation: Chemical Biology Platform, Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Eamon
authors.initials: E
authors.lastname: Comer
authors.forename: Haibo
authors.initials: H
authors.lastname: Liu
authors.forename: Adrien
authors.initials: A
authors.lastname: Joliton
authors.forename: Alexandre
authors.initials: A
authors.lastname: Clabaut
authors.forename: Christopher
authors.initials: C
authors.lastname: Johnson
authors.forename: Lakshmi B
authors.initials: LB
authors.lastname: Akella
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Marcaurelle
mesh_terms: D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry*; D015394:Molecular Structure; D011714:Pyrans / Q000737:chemistry*
chemical_list: D047028:Macrocyclic Compounds; D011714:Pyrans